Targeting PTPN2 to Promote Antitumor Immunity in Triple-Negative Breast Cancer
Abstract
Therapies that use the host immune system to attack tumors have revolutionized cancer management. The most important immune-based therapies target “immune checkpoints.” Immune checkpoints limit the activity of the cells that protect us from invading pathogens and infections (i.e., killer T cells). In the context of cancer, blockade of immune checkpoints can enhance the activity of T cells to help eradicate tumors. The potential for immune-checkpoint blockade is underscored by the high clinical efficacy of antibodies targeting immune checkpoints (such as PD-1 and CTLA-4) that have resulted in cures for some types of tumors. However, despite the fervor, there are two caveats. First, many tumors are not efficiently detected by the immune system. As a consequence, such tumors do not recruit a sufficient number of tumor-specific killer T cells and therefore remain largely unresponsive to checkpoint inhibitors. Second, tumors can “silence” the immune system by various mechanisms and promote resistance to checkpoint inhibitors. Triple-negative breast cancer (TNBC) is an aggressive disease with poor prognosis for which there are no effective therapeutic options. The presence of immune cells, especially T cells, in TNBC has been associated with improved survival. Indeed, there is now compelling evidence that some TNBCs may be more susceptible to immune checkpoint blockade. However, T-cell abundance in TNBC is variable, limiting the widespread utility and efficacy of checkpoint inhibitors. Moreover, although PD-1 checkpoint blockade in combination with chemotherapy can significantly improve the survival of TNBC patients, only a subset of TNBC patients respond to this treatment. Therefore, the overarching goal of this proposal is to define an alternative approach by which to engage and/or reinvigorate the immune system to combat TNBC. Our exciting preliminary studies demonstrate that low levels of an enzyme called PTPN2 in TNBC are associated with increased T-cell numbers and significantly improved patient survival. Consistent with these findings, we demonstrated that the deletion of PTPN2 in TNBC rodent models drives the recruitment of T cells into tumors. Strikingly, we also demonstrated that the deletion of PTPN2 in T cells increases their ability to detect and eliminate cancers in mice. These findings suggest that inhibiting PTPN2 in both tumor cells and T cells will: i) recruit T cells into TNBCs and ii) enhance the ability of these T cells to detect and eliminate tumor cells. In this proposal, we will first establish the therapeutic potential of targeting PTPN2 in tumor cells and T cells to combat TNBC. Specifically, we will use cutting-edge genetic approaches to determine if deletion of PTPN2 in TNBC alone, or TNBC and the immune system (i.e., in T cells) promotes antitumor immunity to eradicate tumors. Second, we will determine if PTPN2 levels in TNBC might be predictive of survival and help stratify patients according to their sensitivity to immune-checkpoint inhibitors. In the short term (3 years), this project will have provided significant insight into the biology of TNBC and the extent to which PTPN2 levels influence TNBC initiation/growth and interactions with the immune system. Importantly, this project will establish if drugs that inhibit PTPN2 might be effective in activating the immune system to combat TNBC; allosteric drugs that are specific for PTPN2 are currently being developed by Principal Investigator Tiganis’ colleagues in Germany (Helmholtz Zentrum München). Finally, this project will have established if PTPN2 levels in TNBC can be used to stratify patients for personalized immunotherapy. In the long term, this work will lead to new therapies for TNBC for service members, veterans, and all women suffering from this otherwise recalcitrant and deadly disease. In particular, this project will develop novel immune-based therapies for patients that would otherwise be unresponsive to existing therapies
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110126
Entities
People
- Tony Tiganis
Organizations
- Monash University
- United States Army